Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][N:38]([CH2:40][C:41]([NH2:43])=[O:42])[CH:39]=2)O1.C(=O)(O)[O-].[Na+]>O1CCOCC1.O.CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH:7]([CH3:26])[CH2:6][C:5]3[C:10](=[CH:11][C:2]([C:35]4[CH:36]=[N:37][N:38]([CH2:40][C:41]([NH2:43])=[O:42])[CH:39]=4)=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[N:15]=1
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: CC1(C)OB(c2cnn(CC(N)=O)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: CC1Cc2ccc(-c3cnn(CC(N)=O)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 16.2 %

Procedure:
A mixture of 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (10 mg, 0.02 mmol; Peak 1, Example 49, Step 7), 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]acetamide (7.2 mg, 0.029 mmol), tetrakis(triphenylphosphine)palladium(0) (1.4 mg, 0.0012 mmol), and sodium bicarbonate (6.0 mg, 0.072 mmol) in 1,4-dioxane (0.2 mL) and water (0.1 mL) was stirred at 90° C. overnight. After cooling, it was diluted with methanol, and purified with RP-HPLC (pH=10 to afford the desired product (1.5 mg). LCMS (M+H)+: m/z=462.3.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[CH3:7][O:8][C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH:21]([OH:26])[C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[CH:12]=[CH:11][CH:10]=1.[NH2:27][C:28]1[N:33]=[C:32]([C:34]2[CH:39]=[CH:38][C:37]([CH2:40][C@H:41]([NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C:42]([OH:44])=[O:43])=[CH:36][CH:35]=2)[CH:31]=[C:30](Cl)[N:29]=1.O>O1CCOCC1.C(OCC)(=O)C>[NH2:27][C:28]1[N:33]=[C:32]([C:34]2[CH:39]=[CH:38][C:37]([CH2:40][C@H:41]([NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C:42]([OH:44])=[O:43])=[CH:36][CH:35]=2)[CH:31]=[C:30]([O:26][CH:21]([C:18]2[CH:19]=[CH:20][C:15]([C:13]3[CH:12]=[CH:11][CH:10]=[C:9]([O:8][CH3:7])[N:14]=3)=[CH:16][CH:17]=2)[C:22]([F:23])([F:24])[F:25])[N:29]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cc(Cl)nc(N)n2)cc1)C(=O)O
Reactant: COc1cccc(-c2ccc(C(O)C(F)(F)F)cc2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc(-c2ccc(C(Oc3cc(-c4ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc4)nc(N)n3)C(F)(F)F)cc2)n1
Temperature: 110 °C
Reaction time: 0.08 h
Yield: 87.6 %

Procedure:
Cs2CO3 (375 mg, 1 mmol) was added to a solution of 1-[4-(6-methoxy-pyridine-2-yl)-phenyl]-2,2,2-trifluoro-ethanol (67 mg, 0.2 mmol) in 10 ml of anhydrous 1,4-dioxane. The mixture was stirred for 5 min, then was added (S)-3-[4-(2-amino-6-chloro-pyrimidin-4-yl)-phenyl]-2-tert-butoxycarbonylamino-propionic acid (78 mg, 0.2 mmol), and the mixture was heated at 110° C. overnight. After cooling, 5 ml water was added and ethyl acetate (20 ml) was used to extract the product. The organic layer was dried over sodium sulfate. The solvent was removed by rotovap to give 112 mg (S)-3-[4-(2-Amino-6-{2,2,2-trifluoro-1-[4-(6-methoxy-pyridin-2-yl)-phenyl]-ethoxy}-pyrimidin-4-yl)-phenyl]-2-tert-butoxycarbonylamino-propionic acid (yield: 88%).
Reaction SMILES: [CH2:1]([C:5]([CH3:13])([CH2:9][CH:10]([CH3:12])[CH3:11])[C:6]([OH:8])=[O:7])[CH:2]([CH3:4])[CH3:3].[CH2:14]([C:16]#[N:17])C.C(Br)C(C)C.S(Cl)([Cl:25])=O.C(N)C>CCOCC.O>[CH2:1]([C:5]([CH3:13])([CH2:9][CH:10]([CH3:12])[CH3:11])[C:6]([Cl:25])=[O:7])[CH:2]([CH3:4])[CH3:3].[CH2:16]([NH:17][C:6](=[O:8])[C:5]([CH2:1][CH:2]([CH3:3])[CH3:4])([CH3:13])[CH2:9][CH:10]([CH3:12])[CH3:11])[CH3:14]
Reactant: CC(C)CC(C)(CC(C)C)C(=O)O
Reactant: O=S(Cl)Cl
Reactant: CCC#N
Agent: CCN
Solvent: O
Solvent: CC(C)CBr
Solvent: CCOCC
Product: CC(C)CC(C)(CC(C)C)C(=O)Cl
Product: CCNC(=O)C(C)(CC(C)C)CC(C)C
Reaction time: 2 h

Procedure:
2-isobutyl-2,4-dimethylpentanoyl chloride (bp. 97°-100°/16 mm) was prepared in the usual way from 2-isobutyl-2,4-dimethylpentanoic acid (prepared by the alkylation of ethyl cyanide with 2 equivalents of isobutyl bromide, followed by hydrolysis) and thionyl chloride. A solution of the acid chloride (1.5 g) in ether (20 ml) was added with stirring to a solution of ethylamine (5 ml of a 70% solution in water) in ether (100 ml). After stirring for 2 hours the ethereal layer was washed with dilute hydrochloric acid and water. The dried (MgSO4) ether solution was concentrated and the residue was recrystallized from petroleum ether (bp. 40°-60°) to give N-ethyl-2-isobutyl-2,4-dimethylpentanamide, mp. 71.5°-72.5°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][CH2:12][N:11]([C@H:14]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][C:22]([S:25]([N:28](S(C5C=CC(OC)=CC=5)(=O)=O)[C:29]5[S:30][CH:31]=[CH:32][N:33]=5)(=[O:27])=[O:26])=[CH:21][CH:20]=4)[C:15]3=[O:45])[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.N1CCOCC1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][CH2:12][N:11]([C@H:14]3[CH2:18][CH2:17][N:16]([C:19]4[CH:20]=[CH:21][C:22]([S:25]([NH:28][C:29]5[S:30][CH:31]=[CH:32][N:33]=5)(=[O:26])=[O:27])=[CH:23][CH:24]=4)[C:15]3=[O:45])[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COc1ccc(S(=O)(=O)N(c2nccs2)S(=O)(=O)c2ccc(N3CC[C@H](N4CC[C@H](c5cc(Cl)cc(Cl)c5)C4)C3=O)cc2)cc1
Solvent: ClCCl
Solvent: C1COCCN1
Product: O=C1[C@@H](N2CC[C@H](c3cc(Cl)cc(Cl)c3)C2)CCN1c1ccc(S(=O)(=O)Nc2nccs2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.3 %

Procedure:
Synthesized according to General Procedure 14. To a stirred solution of 4-[(3R,3′S)-3-(3,5-dichlorophenyl)-2′-oxo-1,3′-bipyrrolidin-1′-yl]-N-(4-methoxyphenylsulfonyl)-N-(thiazol-2-yl)benzenesulfonamide (40 g, 56.5 mmol) in anhydrous DCM (320 mL) under nitrogen at 0° C. was added morpholine (5.42 g, 5.42 mL, 62.2 mmol) dropwise over 5 minutes. The cooling bath was removed and the reaction mixture was allowed to warm up to RT. Stirring was continued at RT for 2 hours during which time the product precipitated. The solid was filtered, washed with ethyl acetate (100 mL) and dried under vacuum to constant weight to provide 4-[(3R,3′S)-3-(3,5-dichlorophenyl)-2′-oxo-1,3′-bipyrrolidin-1′-yl]-N-(thiazol-2-yl)benzenesulfonamide as a white solid (23.50 g, 43.7 mmol, 77% yield). 1H-NMR (400 MHz, DMSO-d6) δ 7.84-7.77 (m, 4H), 7.43-7.37 (m, 3H), 7.24 (d, J=4.6 Hz, 1H), 6.81 (d, J=4.6 Hz, 1H), 3.83-3.72 (m, 2H), 3.58 (t, J=8.8 Hz, 1H), 3.07-2.96 (m, 3H), 2.87 (td, J=8.6, 4.3 Hz, 1H), 2.34-2.20 (m, 2H), 2.11-2.02 (m, 1H) and 1.74 (dt, J=19.9, 6.9 Hz, 1H) ppm. LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=537.3; tR=1.30 min. SFC (Chiralpak AS-H, (0.46×25 cm), 40% methanol (1% DEA)/CO2, 3 mL/min): tR=13.0 min.
Reaction SMILES: [CH2:1]([CH:5]1[CH:10](C)[CH2:9][CH2:8][NH:7][C:6]1=[O:12])[CH2:2]CC.C1(CCN=C=O)C=CC=CC=1.ClS(O)(=O)=O.N.[CH2:30]([CH:34]1[CH:39]([CH3:40])[CH2:38][CH2:37][N:36]([C:41]([NH:43][CH2:44][CH2:45][C:46]2[CH:51]=[CH:50][C:49]([S:52]([NH2:55])(=[O:54])=[O:53])=[CH:48][CH:47]=2)=[O:42])[C:35]1=[O:56])[CH2:31][CH2:32][CH3:33]>CO>[CH:8]1([N:7]=[C:6]=[O:12])[CH2:2][CH2:1][CH2:5][CH2:10][CH2:9]1.[CH2:30]([CH:34]1[CH:39]([CH3:40])[CH2:38][CH2:37][N:36]([C:41]([NH:43][CH2:44][CH2:45][C:46]2[CH:51]=[CH:50][C:49]([S:52]([NH:55][C:6]([NH:7][CH:8]3[CH2:2][CH2:1][CH2:5][CH2:10][CH2:9]3)=[O:12])(=[O:53])=[O:54])=[CH:48][CH:47]=2)=[O:42])[C:35]1=[O:56])[CH2:31][CH2:32][CH3:33]
Reactant: CCCCC1C(=O)N(C(=O)NCCc2ccc(S(N)(=O)=O)cc2)CCC1C
Reactant: CCCCC1C(=O)NCCC1C
Agent: N
Agent: O=C=NCCc1ccccc1
Agent: O=S(=O)(O)Cl
Solvent: CO
Product: CCCCC1C(=O)N(C(=O)NCCc2ccc(S(=O)(=O)NC(=O)NC3CCCCC3)cc2)CCC1C
Product: O=C=NC1CCCCC1

Procedure:
3-butyl-4-methyl-2-oxo-piperidine (m.p. 95°-98° C., prepared according to German Offenlegungsschrift No. 1,023,464) is converted according to Example 2 with phenylethyl-isocyanate to 3-butyl-4-methyl-2-oxo-piperidine-1-(N-2-phenylethyl)-carboxamide, this crude product is converted with chlorosulfonic acid to the sulfochloride, the sulfochloride is converted with ammonia to 4-(2-[3-butyl-4-methyl-2-oxo-piperidine-1-carboxamido)-ethyl]-benzenesulfonamide, m.p. 165°-167° C., from which there is obtained with cyclohexyl isocyanate with N-(4-[2-(3-butyl-4-methyl-2-oxo-piperidine-1-carboxamido)-ethyl]-benzenesulfonyl)-N'-cyclohexyl urea, m.p. 123°-125° C. (from methanol).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[N:9]=[C:8]([S+:10]([O-:18])[CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:17]=3)[NH:7][C:5]=2[CH:6]=1.C=O.[CH3:21][C:22]([S:40][N:41]=[O:42])([CH3:39])[CH2:23][N:24]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:25]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:26].[CH:43]1(N=C=NC2CCCCC2)CCCCC1>C(#N)C>[N:17]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:11][S:10]([C:8]1[NH:7][C:5]2[C:6]([CH2:43][O:30][C:29](=[O:31])[CH2:28][CH2:27][C:25](=[O:26])[N:24]([CH2:23][C:22]([CH3:21])([S:40][N:41]=[O:42])[CH3:39])[CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:1][CH:2]=[CH:3][C:4]=2[N:9]=1)=[O:18]
Reactant: CC(C)(CN(Cc1ccccc1)C(=O)CCC(=O)O)SN=O
Reactant: [O-][S+](Cc1ccccn1)c1nc2ccccc2[nH]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C=O
Solvent: CC#N
Product: CC(C)(CN(Cc1ccccc1)C(=O)CCC(=O)OCc1cccc2nc(S(=O)Cc3ccccn3)[nH]c12)SN=O
Temperature: 70 °C
Reaction time: 3 h
Yield: 55.3 %

Procedure:
A mixture of timoprazole (0.51 g, 1.98 mmol) and 37% formaldehyde (0.80 ml) in acetonitrile (5 ml) was heated at 70° C. for 15 min. The reaction was evaporated to give a solid that was washed twice with ethyl ether/ethyl acetate (4:1) and dissolved in dichloromethane (10 ml). To this solution was added Example 1c (0.65 g, 2 mol), 4-(N—N-dimethylamino)pyridine (10 mg) and dicyclohexylcarbodiimide (1M in dichloromethane, 4 ml, 4 mmol). After stirring at room temperature for 3 hours, the reaction was concentrated under vacuum and the residue was purified by flash column chromatography (ethyl acetate/hexane, 4:1 to 7:1) to afford the title compound (0.65 g, 54.7%) as a green foam. 1H NMR (300 MHz, CDCl3): δ1.82 and 1.91 (2 s, 6H), 2.63 and 2.75 (2br s, 4H), 4.08 and 4.13 (2 s, 2H), 4.70 and 4.85 (2 s, 2H), 4.88 (d, J=14 Hz, 1H), 4.92 (d, J=14 Hz, 1H), 6.36 (d, J=11.4 Hz, 1H), 6.42 (d, =11.4 Hz, 1H), 7.00 and 7.06 (2 d, J=6.8 Hz, 2H), 7.207.64 (m, 9H), 7.81 (d, !=7.7 Hz, 1H), 8.54 (d, J=4 Hz, 1H); 13C NMR (75 MHz, CDCl): δ 27.29, 27.94, 28.88, 52.58, 55.29, 58.18, 62.22, 65.04, 110.73, 120.73, 122.97, 123.85, 125.21, 125.30, 125.58, 127.41, 128.76, 135.03, 135.79, 136.66, 141.70, 149.71, 150.20, 151.66, 171.80, 172.76; LCMS (m/e): 594 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([CH2:12][OH:13])[N:11]=[C:4]2[N:3]=1>ClCCCl.C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([CH:12]=[O:13])[N:11]=[C:4]2[N:3]=1
Reactant: Cc1cc(C)n2nc(CO)nc2n1
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1cc(C)n2nc(C=O)nc2n1
Temperature: 25 °C
Yield: 76.5 %

Procedure:
A slurry of 5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)-methanol (0.3 g, 1.7 mmol) from step 7 above and IBX (1.4 g, 5.0 mmol) in 1,2-dichloroethane (22 mL) was stirred at 80° C. for 18 hours. The reaction was cooled to room temperature, and diluted with 100 mL CH2Cl2. After the solids were removed by filtration, the solvent was removed by rotary evaporation to give a yellow solid. The solid was purified by flash chromatography to give the desired product (229 mg, 77% yield). 1H NMR (CDCl3) δ: 2.72 (s, 3 H), 2.86 (s, 3 H), 6.96 (s, 1 H), 10.24 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[O:16][CH3:17].[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[CH3:17][O:16][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[CH:6]=[CH:7][C:2]=1[NH:1][C:25]([NH:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:26]
Reactant: COc1cc(CC(=O)OC(C)(C)C)ccc1N
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: COc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1ccccc1
Reaction time: 0.75 h
Yield: 102.5 %

Procedure:
To a solution of t-Butyl 4-amino-3-methoxyphenylacetate (0.123 g, 0.52 mmol) in methylene chloride (2.0 mL) was added phenyl isocyanate (60 μL, 0.55 mmol). The reaction was stirred for 45 min then concentrated to afford t-butyl 3-methoxy-4-phenylureidophenylacetate (0.190 g, 100%) as a pale yellow foam: 1H NMR (CDCl3, 300 MHz, ppm) 8.00 (d,11 Hz, 1H) 7.65-6.94 (m, 7H), 6.80 (d, 9.0 Hz, 1H), 6.74 (s, 1H), 3.68 (s, 3H), 3.45 (s, 2H), 1.44 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:7]2)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[Cl:19][CH2:20][C:21](Cl)=[O:22]>C(OCC)(=O)C>[Cl:19][CH2:20][C:21]([CH:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH2:7][NH:8]1)=[O:22]
Reactant: O=[N+]([O-])c1ccc2c(c1)CNC2
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: O=C(CCl)C1NCc2cc([N+](=O)[O-])ccc21
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a suspension in which 42.8 g of 5-nitroisoindoline had been added to an aqueous potassium carbonate solution (108 g of potassium carbonate, 200 ml of water) was added dropwise 200 ml of an ethyl acetate solution containing 31.2 ml of chloroacetyl chloride at 0° C. over 1 hour. The mixture was further stirred at 0° C. for 45 minutes and precipitates were collected by filtration. The obtained solid-was treated with activated carbon in ethyl acetate and recrystallized to obtain 2-chloroacetyl-5-nitroisoindoline.
Reaction SMILES: [C:1]([C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][C:8]=1[C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[C:21]([O:32][CH2:33][C:34]([O:36]CC)=[O:35])[CH:20]=[CH:19]2)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[OH-].[K+]>C1COCC1.O>[C:1]([C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][C:8]=1[C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[C:21]([O:32][CH2:33][C:34]([OH:36])=[O:35])[CH:20]=[CH:19]2)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=O)c1c(-c2ccc3c(-c4ccccc4)c(OCC(=O)OCC)ccc3c2)oc2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCC(=O)c1c(-c2ccc3c(-c4ccccc4)c(OCC(=O)O)ccc3c2)oc2ccccc12

Procedure:
Following the procedure described in Step 4 of Example 6, ethyl 2-{[6-(3-pentanoyl-1-benzofuran-2-yl)-1-phenyl-2-naphthyl]oxy}acetate (0.161 g, 0.318 mmol) was hydrolyzed with potassium hydroxide (0.0693 g, 1.24 mmol) in THF (6 mL) and water (6 mL). 2-{[6-(3-pentanoyl-1-benzofuran-2-yl)-1-phenyl-2-naphthyl]oxy}acetic acid was obtained and was converted to the sodium salt by dissolving (0.103 g, 0.215 mmol) of the acid in methanol (5 mL) and adding 1N sodium hydroxide (0.22 mL, 22 mmol). After standing for 25 minutes, the mixture was solvent evaporated and the residue was rinsed with hexane and dried for 24 hours at 100° C. to give a yellow solid (0.0913 g), mp 272-273° C. (dec.). Mass spectrum (−ESI, [M−H]−) m/z 477. 1HNMR (500 MHz, DMSO-d6): δ8.35 (d, 1H, J=1.7 Hz), 8.05 (t, 2H, J=7.6 Hz), 7.65-7.7 (m, 2H), 7.5-7.55 (m, 3H), 7.35-7.45 (m, 6H), 4.25 (s, 2H), 2.75 (t, 2H, J=7.3 Hz), 1.5-1.55 (m, 2H), 1.1-1.2 (m, 2H), and 0.7 ppm (t, 3H, J=7.4 Hz). Elemental Analysis for C31H26O5Na.0.6H2O: Calculated: C, 72.82; H, 5.16; N, 0.00. Found: C, 72.57; H, 4.92; N, 0.05.
Reaction SMILES: [N:1]1([C:6]2[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[Cl:15][C:16]1[CH:17]=[C:18]([N:23]2[CH2:28][CH2:27][N:26]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:25][CH:24]2[CH2:33][NH2:34])[CH:19]=[CH:20][C:21]=1[Cl:22]>>[Cl:15][C:16]1[CH:17]=[C:18]([N:23]2[CH2:28][CH2:27][N:26]([C:29]([CH3:30])([CH3:31])[CH3:32])[CH2:25][CH:24]2[CH2:33][NH:34][C:10](=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)=[CH:14][CH:13]=2)[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: O=C(O)c1ccc(-n2ccnc2)cc1
Reactant: CC(C)(C)N1CCN(c2ccc(Cl)c(Cl)c2)C(CN)C1
Product: CC(C)(C)N1CCN(c2ccc(Cl)c(Cl)c2)C(CNC(=O)c2ccc(-n3ccnc3)cc2)C1

Procedure:
In a manner similar to preparation 7, react 4-(1H-imidazol-1-yl)benzoic acid, 1,1-carbonyldiimidazole and 1-(3,4-dichlorophenyl)-4-(1,1-dimethylethyl)-2-piperazinemethanamine to obtain the title compound.
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].N1C=CC=CC=1.[CH2:22]([C:29](O)([CH2:33][CH2:34][CH2:35][CH3:36])[C:30]([OH:32])=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:22]([C:29]([O:8][S:1]([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2])([CH2:33][CH2:34][CH2:35][CH3:36])[C:30]([OH:32])=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCCCC(O)(Cc1ccccc1)C(=O)O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCC(Cc1ccccc1)(OS(=O)(=O)C(F)(F)F)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
Triflic anhydride (71 mmoles, 20 g) was added at -27° C. to a solution of pyridine (74 mmoles, 5.9 g) in 150 ml methylene chloride with vigorous stirring. The solution was warmed to room temperature. Benzyl 2-hydroxyhexanoic acid (57 mmoles, 12.65 g) in 15 ml methylene chloride was added over 2 minutes. The solution was stirred for 1 hour and filtered. The filtrate was concentrated, filtered through silica gel eluted with hexane, and evaporated to yield 17.0 g of benzyl 2-(trifluoromethanesuifonylhydroxy)hexanoic acid. (MS)
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Cl:8][C:9]1[N:14]=[C:13]([CH2:15]I)[CH:12]=[C:11]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][C@@H:18]2[CH3:23])[N:10]=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[Cl:8][C:9]1[N:10]=[C:11]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][C@@H:18]2[CH3:23])[CH:12]=[C:13]([CH2:15][S:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[N:14]=1
Reactant: C[C@H]1COCCN1c1cc(CI)nc(Cl)n1
Reactant: Sc1ccncc1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@H]1COCCN1c1cc(CSc2ccncc2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 64.5 %

Procedure:
4-Mercaptopyridine (0.752 g, 6.77 mmol) was added to 2-chloro-4-(iodomethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidine (1.596 g, 4.51 mmol) in acetonitrile (100 mL) at RT under air. DBU (0.3 mL, 2.01 mmol) was then added and the resulting solution was stirred at RT for 2 minutes. The solvent was removed and DCM was added. The reaction mixture was washed sequentially with water, the organic layer dried (MgSO4), filtered and evaporated. The crude product was chromatographed on silica, eluting with 0-2% methanol in DCM. Impure fractions were further chromatographed on silica, eluting with 0-4.5% methanol in DCM and combined with the initial pure fractions to give the desired material as a yellow gum (0.980 g).
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH2:37]([N:39]([CH2:42][C:43]1[S:47][C:46]([C:48]2[O:52][N:51]=[C:50]([C:53]3[CH:58]=[CH:57][C:56]([CH2:59][CH2:60][NH2:61])=[CH:55][CH:54]=3)[N:49]=2)=[CH:45][C:44]=1[CH3:62])[CH2:40][CH3:41])[CH3:38]>CN(C=O)C>[CH2:37]([N:39]([CH2:42][C:43]1[S:47][C:46]([C:48]2[O:52][N:51]=[C:50]([C:53]3[CH:54]=[CH:55][C:56]([CH2:59][CH2:60][NH:61][C:1](=[O:5])[CH2:2][OH:3])=[CH:57][CH:58]=3)[N:49]=2)=[CH:45][C:44]=1[CH3:62])[CH2:40][CH3:41])[CH3:38]
Reactant: CCN(CC)Cc1sc(-c2nc(-c3ccc(CCN)cc3)no2)cc1C
Reactant: O=C(O)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)Cc1sc(-c2nc(-c3ccc(CCNC(=O)CO)cc3)no2)cc1C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of glycolic acid (15 mg, 202 μmol) and DIPEA (35 mg, 270 μmol) in DMF (5 mL) is added HOBt (27 mg, 202 μmol) and EDC hydrochloride (39 mg, 202 μmol) at 0° C. The mixture is stirred for 15 min at 0° C. Then 2-{4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-ethylamine is added and stirring is continued for 1 h at 0° C. The reaction is quenched with water, diluted with sat. aq. NaHCO3 and the mixture is extracted three times with EA. The combined organic extracts are dried over MgSO4, filtered and concentrated. The crude product is purified on prep. TLC plates using DCM containing 10% of 7 N NH3 in methanol to give the title compound (4 mg) as a colourless oil; LC-MS: tR=0.69 min; [M+1]+=429.06.
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[C:25][C:26]([OH:28])=O)=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Cl.C([NH:46]C1C=CC(C#CC(Cl)=O)=CC=1)CCCCCCCCCCCCCCC>>[CH2:1]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[C:25][C:26]([NH2:46])=[O:28])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C#CC(=O)O)cc1
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C#CC(=O)Cl)cc1
Agent: Cl
Product: CCCCCCCCCCCCCCCCNc1ccc(C#CC(N)=O)cc1

Procedure:
A solution of 4-hexadecylaminophenylpropiolic acid is converted to 4-hexadecylaminophenylpropiolic acid chloride hydrochloride as described in Example 18. After evaporation of the solvent, the unpurified acid chloride is slurried in methylene chloride and treated with anhydrous ammonia as in Example 31. Workup as described therein provides the title compound. Likewise, 4-(hexadecylamino)cinnamamide is prepared from 4-(hexadecylamino)cinnamic acid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH:21]=[CH2:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=C[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C=CC1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ru]Cl.ClCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH:21]=[CH:22][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=Cc1ccccc1
Reactant: C=CC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: Cl[Ru]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C(=CC1CN(Cc2ccccc2)CCN1Cc1ccccc1)c1ccccc1
Reaction time: 24 h

Procedure:
Combine 1,4-dibenzyl-2-vinyl-piperazine (200.0 mg, 0.68 mmol), styrene (142.5 mg, 1.37 mmol), bis(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride (168.8 mg, 0.21 mmol), and dichloromethane (8 mL) and stir at reflux. After 24 hours, the reaction mixture was filtered and reduced to residue. The title compound was observed by LC/MS: mass spectrum (ion spray): m/z=369.1 (M+1); Rf=0.49 (hexanes/ethyl acetate (40:60)).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8](=[C:14]([F:16])[F:15])[CH2:9][CH2:10][C:11](O)=[O:12].O>C(OCC)C>[F:7][C:8](=[C:14]([F:16])[F:15])[CH2:9][CH2:10][CH2:11][OH:12]
Reactant: O=C(O)CCC(F)=C(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: OCCCC(F)=C(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.1 %

Procedure:
To a stirred suspension of 0.4 gram (0.01 mole) of lithium aluminum hydride in 20 ml of diethyl ether was added dropwise a solution of 1.5 grams (0.01 mole) of 4,5,5-trifluoro-4-pentenoic acid in 30 ml of diethyl ether. Upon completion of addition the reaction mixture was stirred at ambient temperature for one hour, then 20 ml of water was added carefully. The mixture was filtered and the filtrate concentrated under reduced pressure to give 0.8 gram of 4,5,5-trifluoro-4-penten-1-ol as an oil. The nmr and the ir spectra were consistent with the proposed structure.